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Background:  Non-nucleoside reverse transcriptase inhibitors (NNRTI) are potent components of combination antiretroviral regimens. Currently available NNRTI regimens are limited by the emergence of broad cross resistance to NNRTI and toxicities. BILR 355 BS is a next-generation NNRTI with potent antiviral activity.

Methods:  The in vitro inhibitory activity (IC₅₀ value) and anti HIV-1 activity (EC₅₀ value) of BILR 355 BS were determined against wild type and recombinant viruses containing 1 or more mutations that confer phenotypic resistance to NNRTI. This panel of viruses was selected based on the clinical prevalence of NNRTI-resistant mutants, and included K103N, Y181C, G190A, K103N/Y181C, K103N/V108I, K103N/P225H, and L100I/K103N. BILR 355 BS was also tested against a broad panel of HIV-1 isolates from various clades (A, B, C, D, G, O, A/E, A/G) originating from treatment-naïve patients. Single and multiple dose healthy male volunteer studies have been conducted with BILR 355 BS + RTV 100 mg (7 to 11 days), to determine its pharmacokinetics, safety and tolerability.

Results:  The EC₅₀ of BILR 355 against wild type HIV-1 is 0.26 ng/mL and against common NNRTI-resistant viruses ranges from 1.5 to 13 ng/mL for the more clinically common single and double NNRTI mutations. BILR 355 BS maintains potent antiviral activity against the panel of HIV-1 clades tested (median EC₅₀ = 1.3 ng/mL) but is inactive against HIV-2. A serum shift of 2-fold in 50% human serum will limit the effect of protein binding. Orally administered single-dose BILR 355 BS resulted in modest plasma levels and T_1/2 of 2 hours. Exposure is increased when ritonavir (RTV) 100 mg is added:  C_max by approximately 2.3- to 5-fold, and T_1/2 by 3.5- to 5.5-fold. Multiple-dose exposure at 150 mg once daily + RTV 100 mg once daily results in C_max-ss 870 ng/mL (single-dose 130), Cp24_ss 279 ng/mL (single-dose 54), and T_1/2 of 16 to 17 hours. Time to steady state is 5 to 6 days. With the exception of 1 subject with a transient asymptomatic grade 3 ALT elevation in the 25-mg-dose cohort, there have been no significant clinical or laboratory safety abnormalities observed to date.

Conclusions:  BILR 355 BS displays an excellent antiretroviral profile against HIV-1 wild type and NNRTI-resistant mutants and promising biopharmaceutical properties. When co-administered with RTV, BILR 355 BS has favorable human pharmacokinetics and safety profiles for as long as 11 days of exposure. These data support the continued development of BILR 355 BS as a novel NNRTI with activity against viruses resistant to first generation NNRTI.

Keywords: Nonnucleoside reverse transcriptase inhibitor; Novel drug; Antiretroviral drug